Exhaled nitric oxide (NO) is a promising non-invasive tool to assess lung function, particularly in inflammatory diseases such as asthma. Traditional techniques, such as spirometry, are aimed at examining physical features of the lungs, such as airway caliber. In contrast, exhaled NO is derived from the lung tissue, and is thus uniquely positioned to provide information on inflammatory processes. NO exchange occurs in both the airways and alveolar regions. The current model to describe NO exchange utilizes a single path trumpet model, despite significant evidence that ventilation patterns and inflammation are heterogeneous in asthma. We hypothesize that ventilation and inflammation heterogeneity in both the conducting airways (bronchi and bronchioles) and the acinar region (respiratory bronchioles to alveoli) of the lungs impacts the exhaled concentration of NO. This effect is particularly important in asthmatics, and influences the interpretation of exhaled NO as a non-invasive marker of inflammation to guide therapy. This proposal seeks to first characterize experimentally the ventilation and inflammation heterogeneity in both proximal and peripheral regions of the lungs in a group of both healthy and asthmatic subjects at baseline and during bronchoconstriction using three different, but complimentary, techniques: Multiple breath nitrogen washout, positron emission tomography (PET) imaging of 13NN washout and [18F]-fluordeoxyglucose (18FDG) uptake, and high resolution computed tomography of the airway tree (Aim 1). Then, the experimental observations will used to develop and validate a quantitative description (mathematical model) of NO exchange in the lungs (Aim 2). Finally, the new model will tested (or translated) in a group of children with asthma, and its impact on the clinical management and control of symptoms examined (Aim 3). This path of investigation will move us closer towards realizing the potential of exhaled NO as a simple and non-invasive research and clinical tool. PUBLIC HEALTH RELEVANCE: Asthma is one of the most prevalent chronic diseases in the United States. Diagnosis and management remain challenging due to the heterogeneous nature of the disease, and the lack of simple metabolic indices of disease status. This proposal seeks to understand the mechanisms which control the amount of nitric oxide in the exhaled breath, a metabolic marker of inflammation. Understanding the source of exhaled nitric oxide may significantly impact the clinical management of the disease.